In a randomized, Phase III head-to-head trial of two bisphosphonates, intravenous zoledronic acid was more effective than oral clodronic acid in reducing the risk of skeletal-related events (SREs), particularly vertebral fractures, in patients with multiple myeloma.
An equally important finding of the British Medical Research Council (MRC) Myeloma IX trial was that the earlier treatment was started, including from time of diagnosis, the greater the reduction in risk. There was approximately a 50% reduction in the number of patients who develop SREs during the disease course when treated with zoledronic acid at the time of diagnosis.
In addition, patients benefited from treatment irrespective of bone disease status at baseline.
This report, published in the August issue of Lancet Oncology (2011;12:743-751) follows the first MRC Myeloma IX report, in 2010, which showed that zoledronic acid reduced mortality by 16%; extended median overall survival by 5.5 months; significantly improved progression-free survival by 12%; and increased medial progression-free survival by 2.0 months, compared with clodronic acid (Lancet 2010;376:1989-99).
The 2010 report also showed that the survival advantage was independent of zoledronic acid's ability to prevent skeletal-related injuries.
This new report shows the benefits in more detail, including a longer time to first skeletal-related event and incidence of the events.
First author Gareth J. Morgan, MD, PhD, Head of the Myeloma Unit at Royal Marsden Hospital and Professor of Haemato-Oncology at the Institute of Cancer Research, said the new study also adds to the 2010 data by showing that a longer period of treatment also yields greater benefits in reduction of skeletal-related events.
Dr. Morgan shared joint first authorship with J. Anthony Child, MD, Professor in the Clinical Trials Research Unit at the University of Leeds. Based on the data, “we should introduce these agents early in the course of the disease when the patient is first diagnosed,” Dr. Morgan said in a telephone interview. “And the trial data support continuing the drugs until disease progression.”
Another new finding was that bone disease could be reduced by bisphosphonate treatment even if the patient did not have bone disease at presentation.
“Previously people with no bone lesions weren't considered for treatment with these agents, but I think we have shown convincingly that you can reduce the rates of SREs in patients even in patients who don't have bone disease at baseline,” Dr. Morgan said. “That's important, because if patients start out without bone lesions they don't get bone pain, but once they do have an SRE there is a chance it will impair their quality of life.”
Most treatment guidelines have advised stopping bisphosphonates in multiple myeloma at two years, he noted. “But we did cut-point analyses at one, two, and three years, for people still on the bisphosphonates at those times, and it seemed that the longer you are on the bisphosphonate, the greater the benefit.”
Six-Year Data Will Be Reported at ASH
The median time on treatment was approximately three years, he said, adding that his group is planning to present six-year data at this year's American Society of Hematology Annual Meeting, in December.
On a financial note, Dr. Morgan pointed out that the median time to disease progression in this trial was still only just over a year, so the overall cost to a health care system is not overly high by continuing people on treatment.
Active Even with Baseline Lesions
In the trial, 1960 patients were randomly assigned to zoledronic acid or clodronic acid. At a median follow-up of 3.7 years, patients in the zoledronic acid group had a lower incidence of skeletal-related events than those in the clodronic acid group did—265 patients (27%) vs 346 patients (35%) respectively.
Among patients with bone lesions at baseline, 233 of 668 patients (35%) in the zoledronic acid group experienced skeletal-related events vs 292 of 682 patients (43%) in the clodronic acid group.
Among those without bone lesions at baseline, 29 of 302 patients in the zoledronic acid group (10%) had events, compared with 48 of 276 (17%) in the clodronic acid group.
And fewer patients in the zoledronic acid group had vertebral fractures — 5% in the zoledronic acid group vs 9% for clodronic acid patients.
While a drop from 35% incidence to 27% is a great improvement, that means that about one quarter of the trial patients are still suffering from bone lesions.
Dr. Morgan said several agents are already available that inhibit bone resorption, and so the next challenge is to develop drugs that stimulate new bone formation. He mentioned two promising agents—an activin-a inhibitor and an antibody called BHQ822.
“In the past, 55% of myeloma patients would get bone lesions before their disease progressed, and by the end of the disease, 100% had a bone lesion,” he said. “Their spines could shrink six inches.
“We're not seeing that in the clinic anymore because the bisphosphonates have been effective, but to get to the next stage we have to look at bone anabolic agents.”
Ongoing Debate: What about in CR?
There has been an ongoing debate about whether bisphosphonate treatment in myeloma should be stopped when the patient achieves a complete remission (CR), Dr. Morgan said.
“We are going to try to address that as a question [in a future trial], but it seems there is benefit even in patients in CR,” he said.
He added that in his opinion, giving monthly bisphosphonate treatment to a patient in CR after bone marrow transplant might be too frequent: “In my practice, which is not based on the trial result, I try and continue [the bisphosphonate during complete remission], but to give it less frequently—every two months instead of every month.”
He also said he would definitely continue treatment after disease progression. “During active disease is when you are resorbing bones,” he said. “While I can't use the trial data to justify that, because it was very much a study predicated on analyzing people up until disease progression, the implications are that you should continue it even until people die. Which is what I do.”
Thalidomide, Clodronate Not Used Much in US
Thalidomide was the anti-myeloma agent used in MRC Myeloma IX, and Dr. Morgan said that it is a standard regimen for myeloma in many countries in the world, though not the United States. Clodronate is not approved for this indication in the US.
Zoledronic acid is approved in the UK and in the US. A third bisphosphonate, pamidronate, is sold generically, at a lower cost than zoledronic acid, but there is much less trial data on pamidronate, Dr. Morgan said.
“We're addressing now the question of switching to a Revlimid induction. There is evidence that Revlimid and Velcade are active against bone disease, and the question people ask is whether there is benefit to adding a bisphosphonate to these new agents. My suspicion is that it will be additive to the anti-bone effects of the novel agents and that it will be safe.”
Relevant in the US?
A US hematologist said the trial results are nonetheless relevant in this country. David Siegel, MD, PhD, Chief of the, Myeloma Division at John Theurer Cancer Center of Hackensack (NJ) Medical Center, said he did not believe the major point of this article on MRC Myeloma IX is the distinction between zoledronic acid and clodronate.
To some extent, he said in a telephone interview, the clodronic arm in the trial could be viewed as a control arm. In the US, most oncologists use zoledronate and pamidronate in management of patients with multiple myeloma, so there really never has been a debate between zoledronic acid and clodronic acid, he said.
“The issue we have been debating is whether we should continue using these drugs at all beyond the very acute situation. Ten years ago we did not recognize there were any toxicities associated with these drugs, so we used them quite liberally and didn't feel there was a strong reason for not using.”
But then it was recognized that pamidronate and zoledronate both could cause kidney problems, he said. More recently the observation was made that bisphosphonates can cause osteonecrosis of the jaw, and the use of these drugs was to a large extent curtailed.
This new data shows zoledronate superior to clodronate, but one could make the assumption that if the randomization were between zoledronate and nothing, it would still be obvious that zoledronate protects the skeleton of patients with multiple myeloma, even in patients who don't have obvious skeletal disease, he said.
“The important message is that there is a cost to being less aggressive with these drugs, and I think this will change the mindset behind these decisions,” Dr. Siegel said.
He also noted that lenalidomide and bortezomib have largely supplanted thalidomide in the US, so that part of MRC Myeloma IX is not entirely relevant to the United States.
True Anti-Myeloma Effect
Also asked for his opinion for this article, Paul G. Richardson, MD, Clinical Director of the Jerome Lipper Myeloma Center at Dana-Farber Cancer Institute, said the benefits seen in MRC Myeloma IX in those patients without overt bone disease are compelling in that they support a true anti-myeloma effect from this approach.
“The study is the largest of its kind and shows a clear overall survival advantage to IV aminobisphosphonate therapy in multiple myeloma. It also frames the scope of complications nicely to help assess risk versus benefit.”
He said the advantage of starting bisphosphonate therapy at diagnosis was clear cut. “You don't have to wait for overt bone disease. Starting patients earlier makes complete sense. You're intervening with a strategy that's on the cellular and molecular level, so why should you have to wait until there are florid lesions?”
Dr. Richardson said he also saw a role for continuing bisphosphonate treatment beyond complete remission, but further study would be needed to define the optimal duration of therapy.
In an accompanying Commentary in the same issue of the journal, Evangelos Terpos, MD, and Meletios A. Dimopoulos, MD, of the University of Athens School of Medicine, wrote that the results of the MRC Myeloma IX trial are extremely important for current clinical practice.
They noted that the British Society Committee for Standards in Haematology and the UK Myeloma Forum have already recommended that zoledronic acid should be given to all patients with symptomatic multiple myeloma.
Drs. Terpos and Dimopoulos listed several questions that need to be addressed in future trials:
* Would zoledronic acid continue to be superior if drugs such as bortezomib or lenalidomide were given as initial treatment?
* Is zoledronic acid superior to pamidronate in the era of new drugs?
* Is zoledronic acid recommended for all patients with symptomatic myeloma or only those with abnormal findings on PET, CT, or MRI?
* What should be the duration of treatment?
* And can treatment be administered for more than two years, and if so, in which patients?